背景：如今，耐甲氧西林金黄色葡萄球菌(MRSA)和耐万古霉素金黄色葡萄球菌(VRSA)菌株的出现极大地限制了针对该微生物的治疗选择.因此,在这项研究中，我们旨在发现针对金黄色葡萄球菌的新的药物靶点和抑制剂。
方法：本研究包括两个主要部分。在上游评估中，经过全面的核心蛋白质组分析，选择与人类蛋白质组没有相似性的必需细胞质蛋白。然后选择金黄色葡萄球菌代谢组特异性蛋白，并使用DrugBank数据库确定了新的药物靶标。在下游分析中，使用StreptomeDB文库和AutoDockVina软件,进行了基于结构的虚拟筛选方法,以揭示针对腺嘌呤N1(m1A22)-tRNA甲基转移酶(TrmK)的潜在命中化合物.基于ADMET性质分析结合亲和力>-9kcal/mol的化合物。最后,命中化合物是根据Lipinski的5规则（RO5）选择的。
结果：三种蛋白质，包括甘氨酸糖基转移酶（FemA），TrmK,和七苯乙烯基焦磷酸合酶亚基A（HepS1），根据PDB文件的可用性及其在金黄色葡萄球菌生存中的重要作用，被选择为可行和有前途的药物靶标。最后,七个命中化合物，包括诺卡利嗪A，Geninthiocin_D,Citreamicin_delta,喹诺酮,雷切霉素,将Di-AFN_A1和萘霉素_K引入TrmK的结合腔，作为一个可行的药物靶点。
结论：本研究的结果提供了针对金黄色葡萄球菌的三个可行的药物靶标。在下文中，引入了七个命中化合物作为TrmK的潜在抑制剂，和Geninthiocin_D被确定为最理想的药物。然而,需要进行体内和体外研究以确认这些药物对S.areus的抑制作用。
Nowadays, the emergence of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant S. aureus (VRSA) strains has dramatically restricted the treatment options against this microorganism.
In this study, we aimed to discover new drug targets and inhibitors against S. aureus.
This study consists of two major sections. In the upstream evaluation, after a comprehensive coreproteome analysis, essential cytoplasmic proteins with no similarity to the human proteome were selected. Then the S. aureus metabolome-specific proteins were selected, and novel drug targets were identified using the DrugBank database. In the downstream analysis, a structure-based virtual screening approach was performed to reveal potential hit compounds against adenine N1 (m(m1A22)-tRNA methyltransferase (TrmK) using the StreptomeDB library and AutoDock Vina software. The compounds with a binding affinity > -9 kcal/mol were analyzed based on ADMET properties. Finally, the hit compounds were selected based on Lipinski\'s rule of five (RO5).
Three proteins, including glycine glycosyltransferase (FemA), TrmK, and heptaprenyl pyrophosphate synthase subunit A (HepS1), were selected as feasible and promising drug targets based on PDB file availability and their essential role in the survival of the S. aureus. Finally, seven hit compounds, including Nocardioazine_ A, Geninthiocin_D, Citreamicin_delta, Quinaldopeptin, Rachelmycin, Di-AFN_A1 and Naphthomycin_ K were introduced against the binding cavity of TrmK, as a feasible drug target.
The results of this study provided three feasible drug targets against S. aureus. In the following, seven hit compounds were introduced as potential inhibitors of TrmK, and Geninthiocin_D was identified as the most desirable agent. However, in vivo and in vitro investigations are needed to confirm the inhibitory effect of these agents on S. aureus.
